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Adenoid cystic carcinoma of minor salivary glands (AdCCmSG) represents a 'rarity in the rarity,' posing a clinical challenge in lack of standardized, evidence-based recommendations. At present, AdCCmSG management is mostly translated from major salivary gland cancers (MSGCs). Ideally, AdCCmSG diagnostic-therapeutic workup should be discussed and carried out within a multidisciplinary, high-expertise setting, including pathologists, surgeons, radiation oncologists and medical oncologists. The present review provides an overview of epidemiology and pathologic classification. Moreover, the most recent, clinically relevant updates in the treatment of AdCCmSG (Pubmed searches, specific guidelines) are critically discussed, aiming to a better understanding of this rare pathologic entity, potentially optimizing the care process, and offering a starting point for reflection on future therapeutic developments. The management of rare cancers is often hindered by limited data and clinical trials, lack of evidence-based guidelines, and hardly represented disease heterogeneity, which cannot be successfully tackled with a 'one-size-fits-all' approach. Our goal is to address these potential pitfalls, providing an easy-to-use, updated, multidisciplinary collection of expert opinions concerning AdCCmSG management as of today's clinical practice. We will also cover the most promising future perspectives, based on the potential therapeutic targets highlighted within AdCCmSG's molecular background. [ABSTRACT FROM AUTHOR]

Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

Abstract The MV1 and MV2 subtypes of sporadic Creutzfeldt–Jakob disease (sCJD) are linked to the heterozygous methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene. MV2 is phenotypically heterogeneous, whereas MV1, due to its low prevalence, is one of the least well characterized subtypes. In this study, we investigated the biochemical properties of PrPSc and phenotypic expression of cases diagnosed as sCJD MV1 and MV2. We describe four MV2 histotypes: 2C, with cortical (C) coarse pathology; 2K, with kuru (K) plaque deposits; 2C-K, with co-existing C and K histotypic features; and the novel histotype 2C-PL that mimics 2C in the cerebral cortex and cerebellum, but exhibits plaque-like (PL) PrP deposits in subcortical regions (e.g., basal nuclei, thalamus and midbrain). Histotype prevalence is highest for 2C-K (55%), intermediate for 2C (31%), and lowest for 2C-PL and 2K (7%). Nearly every MV2 case expressed both PrPSc types, with T2 being the predominant type (“MV2-1”). MV1 cases typically show a rapid disease course (≤ 4 months), and feature the 1C histotype, phenotypically identical to sCJDMM1. Co-existing PrPSc types, with T1 significantly exceeding T2 (“MV1-2”), are detected in patients diagnosed as MV1 with longer disease courses. We observed four histotypes among MV1-2 cases, including two novel histotypes: 1V, reminiscent of sCJDVV1; 1C-2C, resembling sCJDMM1-2 with predominant MM1 histotypic component; and novel histotypes 1C-2PL and 1C-2K, overall mimicking 1C in the cerebral cortex, but harboring T2 and plaque-like PrP deposits in subcortical regions (1C-2PL), and T2 and kuru plaques in the cerebellum (1C-2K). Lesion profiles of 1C, 1V, and 1C-2C are similar, but differ from 1C-2PL and 1C-2K, as the latter two groups show prominent hippocampal and nigral degeneration. We believe that the novel “C-PL” histotypes are distinct entities rather than intermediate forms between “C” and “C-K” groups, and that 1C-2PL and 1C-2K histotypes may be characterized by different T1 variants of the same size.

Simple Summary: Testicular cancer is characterized by an excellent prognosis; long survival, however, requires careful monitoring, also due to the possibility of developing second tumors. Seminoma has a better prognosis, even many years after diagnosis, but also a greater possibility of developing second tumors. Non-seminoma presents an increased risk, especially among patients over 40. This study investigated the incidence, mortality, and 5-year survival rates of testicular cancers diagnosed in a northern Italian province, which were eventually associated with previous or subsequent extratesticular neoplasms. Cases from 1996 to 2020 were examined by age and histotype (seminoma vs. non-seminoma). The standardized incidence rate was calculated using the European population, and the annual percent change (APC) was reported. The five-year relative survival was estimated using the Pohar Perme method. The association with the second neoplasm was also evaluated. In our study, 385 patients with testicular cancer were included, most of whom were aged between 30 and 40 years. The non-seminoma and seminoma groups accounted for 44% and 18% of younger adults, respectively. The incidence rate increased during the study period (APC 1.6*); however, it increased in seminomas (APC 2.3*) but not in non-seminomas (APC −0.1). Conversely, the mortality rate remained constantly low either overall or in each of the two groups. The overall 5-year survival rate of testicular cancer patients was 95% (99% and 88% for seminomas and non-seminomas, respectively). Primary extratesticular tumors were documented in 37 cases, 18 after and 19 before the testicular cancer diagnosis. Our study confirms that the increased incidence and excellent survival rate are the prerogative of seminomas. [ABSTRACT FROM AUTHOR]

Simple Summary: Effective personalised cancer therapy depends on an understanding of the fundamental biological differences between tumours. Such differences may include the activation or suppression of molecular pathways involved in the development and regulation of the normal cells that give rise to the cancer of interest. One such candidate pathway in mammary/breast cancer is NOTCH signalling. In a mouse model of mammary cancer, which normally develops four different histological tumour types upon knockout of the Pten and p53 tumour suppressor genes in the mammary gland, the additional knockout of the Notch1 or Notch2 genes did not alter the kinetics of tumour onset but did significantly change the relative proportions of different tumour types. This was accompanied by changes in PI3K/AKT signalling. We suggest PI3K/AKT and NOTCH signalling interact to determine mouse mammary tumour histotype. A better understanding of the mechanisms generating tumour heterogeneity will allow better targeting of current therapies, identify potential resistance mechanisms and highlight new approaches for therapy. We have previously shown that in genetically modified mouse models carrying conditional oncogenic alleles, mammary tumour histotype varies depending on the combination of alleles, the cell type to which they are targeted and, in some cases, reproductive history. This suggests that tumour heterogeneity is not a purely stochastic process; rather, differential activation of signalling pathways leads to reproducible differences in tumour histotype. We propose the NOTCH signalling pathway as one such pathway. Here, we have crossed conditional knockout Notch1 or Notch2 alleles into an established mouse mammary tumour model. Notch1/2 deletion had no effect on tumour-specific survival; however, loss of Notch alleles resulted in a dose-dependent increase in metaplastic adenosquamous carcinomas (ASQCs). ASQCs and adenomyoepitheliomas (AMEs) also demonstrated a significant increase in AKT signalling independent of Notch status. Therefore, the NOTCH pathway is a suppressor of the ASQC phenotype, while increased PI3K/AKT signalling is associated with ASQC and AME tumours. We propose a model in which PI3K/AKT and NOTCH signalling act interact to determine mouse mammary tumour histotype. [ABSTRACT FROM AUTHOR]

Contemporary population‐based data on ovarian cancer survival using current subtype classifications and by surgical status are sparse. We evaluated 1‐, 3‐, 5‐ and 7‐year relative (and overall) survival, and excess hazards in patients with borderline tumors or invasive epithelial ovarian cancer diagnosed 2012 to 2021 in a nationwide registry‐based cohort in Norway. Outcomes were evaluated by histotype, FIGO stage, cytoreduction surgery and residual disease. Overall survival was evaluated for non‐epithelial ovarian cancer. Survival of women with borderline ovarian tumors was excellent (≥98.0% 7‐year relative survival). Across all evaluated invasive epithelial ovarian cancer histotypes, 7‐year relative survival for cases diagnosed with stages I or II disease was ≥78.3% (stage II high‐grade serous). Survival for ovarian cancers diagnosed at stage ≥III differed substantially by histotype and time since diagnosis (eg, stage III, 5‐year relative survival from 27.7% [carcinosarcomas] to 76.2% [endometrioid]). Overall survival for non‐epithelial cases was good (91.8% 5‐year overall survival). Women diagnosed with stage III or IV invasive epithelial ovarian cancer and with residual disease following cytoreduction surgery had substantially better survival than women not operated. These findings were robust to restriction to women with high reported functional status scores. Patterns for overall survival were similar to those for relative survival. We observed relatively good survival with early stage at diagnosis even for the high grade serous histotype. Survival for patients diagnosed at stage ≥III invasive epithelial ovarian cancer was poor for all but endometrioid disease. There remains an urgent need for strategies for risk reduction and earlier detection, together with effective targeted treatments. [ABSTRACT FROM AUTHOR]

The MV1 and MV2 subtypes of sporadic Creutzfeldt–Jakob disease (sCJD) are linked to the heterozygous methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene. MV2 is phenotypically heterogeneous, whereas MV1, due to its low prevalence, is one of the least well characterized subtypes. In this study, we investigated the biochemical properties of PrPSc and phenotypic expression of cases diagnosed as sCJD MV1 and MV2. We describe four MV2 histotypes: 2C, with cortical (C) coarse pathology; 2K, with kuru (K) plaque deposits; 2C-K, with co-existing C and K histotypic features; and the novel histotype 2C-PL that mimics 2C in the cerebral cortex and cerebellum, but exhibits plaque-like (PL) PrP deposits in subcortical regions (e.g., basal nuclei, thalamus and midbrain). Histotype prevalence is highest for 2C-K (55%), intermediate for 2C (31%), and lowest for 2C-PL and 2K (7%). Nearly every MV2 case expressed both PrPSc types, with T2 being the predominant type ("MV2-1"). MV1 cases typically show a rapid disease course (≤ 4 months), and feature the 1C histotype, phenotypically identical to sCJDMM1. Co-existing PrPSc types, with T1 significantly exceeding T2 ("MV1-2"), are detected in patients diagnosed as MV1 with longer disease courses. We observed four histotypes among MV1-2 cases, including two novel histotypes: 1V, reminiscent of sCJDVV1; 1C-2C, resembling sCJDMM1-2 with predominant MM1 histotypic component; and novel histotypes 1C-2PL and 1C-2K, overall mimicking 1C in the cerebral cortex, but harboring T2 and plaque-like PrP deposits in subcortical regions (1C-2PL), and T2 and kuru plaques in the cerebellum (1C-2K). Lesion profiles of 1C, 1V, and 1C-2C are similar, but differ from 1C-2PL and 1C-2K, as the latter two groups show prominent hippocampal and nigral degeneration. We believe that the novel "C-PL" histotypes are distinct entities rather than intermediate forms between "C" and "C-K" groups, and that 1C-2PL and 1C-2K histotypes may be characterized by different T1 variants of the same size. [ABSTRACT FROM AUTHOR]

ObjectiveAlthough ovarian cancer is a deadly disease, approximately a third of women survive ≥9 years after diagnosis. The factors associated with achieving long-term survival are not well understood. In this study, data from the Surveillance, Epidemiology, and End Results (SEER) program were used to determine predictors of survival trajectories among women with epithelial ovarian cancer and across histotype (high-grade serous carcinoma (HGSC) and non-HGSC).MethodsData on 35,868 women diagnosed with epithelial ovarian cancer in 2004-2016 were extracted from SEER. Extended Cox proportional hazards regression was used to estimate overall and histotype-specific associations between patient and tumor characteristics and all-cause mortality within each survival time (t) interval (t 70 years at diagnosis, where a high risk of mortality was observed in both the t

isomiRs, the sequence‐variants of microRNA, are known to be tissue and cell type specific but their physiological role is largely unknown. In our study, we explored for the first time the expression of isomiRs across different Stage I epithelial ovarian cancer (EOC) histological subtypes, in order to shed new light on their biological role in tumor growth and progression. In a multicentric retrospective cohort of tumor biopsies (n = 215) we sequenced small RNAs finding 971 expressed miRNAs, 64% of which are isomiRs. Among them, 42 isomiRs showed a clear histotype specific pattern, confirming our previously identified miRNA markers (miR192/194 and miR30a‐3p/5p for mucinous and clear cell subtypes, respectively) and uncovering new biomarkers for all the five subtypes. Using integrative models, we found that the 38% of these miRNA expression alterations is the result of copy number variations while the 17% of differential transcriptional activities. Our work represents the first attempt to characterize isomiRs expression in Stage I EOC within and across subtypes and to contextualize their alterations in the framework of the large genomic heterogeneity of this tumor. [ABSTRACT FROM AUTHOR]

(1) Background: Ovarian cancer (OC) and Parkinson's disease (PD) represent a huge public health burden. The relationship of these two diseases is suggested in the literature while not fully understood. To better understand this relationship, we conducted a bidirectional Mendelian ran-domization analysis using genetic markers as a proxy. (2) Methods: Utilizing single nucleotide polymorphisms associated with PD risk, we assessed the association between genetically predicted PD and OC risk, overall and by histotypes, using summary statistics from previously conducted genome-wide association studies of OC within the Ovarian Cancer Association Consortium. Similarly, we assessed the association between genetically predicted OC and PD risk. The inverse variance weighted method was used as the main method to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations of interest. (3) Results: There was no significant association between genetically predicted PD and OC risk: OR = 0.95 (95% CI: 0.88–1.03), or between genetically predicted OC and PD risk: OR = 0.80 (95% CI: 0.61–1.06). On the other hand, when examined by histotypes, a suggestive inverse association was observed between genetically predicted high grade serous OC and PD risk: OR = 0.91 (95% CI: 0.84–0.99). (4) Conclusions: Overall, our study did not observe a strong genetic association between PD and OC, but the observed potential association between high grade serous OC and reduced PD risk warrants further investigation. [ABSTRACT FROM AUTHOR]

BackgroundPolycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer.MethodsUtilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls).ResultsAn inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations.ConclusionOur study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.

Abstract The methionine (M)—valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion strains, named M1, M2C, M2T, V2, and V1, based on two major conformations of the pathological prion protein (PrPSc, type 1 and type 2), and the codon 129 genotype determining susceptibility and propagation efficiency. While the most frequent sCJD strains have been described in codon 129 homozygosis (MM1, MM2C, VV2) and heterozygosis (MV1, MV2K, and MV2C), the V1 strain has only been found in patients carrying VV. We identified six sCJD cases, 4 in Catalonia and 2 in Italy, carrying MV at PRNP codon 129 in combination with PrPSc type 1 and a new clinical and neuropathological profile reminiscent of the VV1 sCJD subtype rather than typical MM1/MV1. All patients had a relatively long duration (mean of 20.5 vs. 3.5 months of MM1/MV1 patients) and lacked electroencephalographic periodic sharp-wave complexes at diagnosis. Distinctive histopathological features included the spongiform change with vacuoles of larger size than those seen in sCJD MM1/MV1, the lesion profile with prominent cortical and striatal involvement, and the pattern of PrPSc deposition characterized by a dissociation between florid spongiform change and mild synaptic deposits associated with coarse, patch-like deposits in the cerebellar molecular layer. Western blot analysis of brain homogenates revealed a PrPSc type 1 profile with physicochemical properties reminiscent of the type 1 protein linked to the VV1 sCJD subtype. In summary, we have identified a new subtype of sCJD with distinctive clinicopathological features significantly overlapping with those of the VV1 subtype, possibly representing the missing evidence of V1 sCJD strain propagation in the 129MV host genotype.

Introduction: Ovarian cancer (OC) is the leading cause of gynecological cancer-related death. Of the main OC histologic subtypes, invasive mucinous carcinomas (MC) account for only 3% of OC cases and are frequently associated with favorable prognosis. Nevertheless, MCs differ greatly from the other OC histotypes in clinical, pathological, and biological behavior. However, the origin and molecular pathogenesis of MC are not yet fully understood. Therefore, identification of novel diagnostic markers could potentially facilitate early diagnosis of OC, particularly the MC histotype, thereby leading to the development of histotype-specific treatment regimens and improved survival rates. Methods: In the present study, Trefoil factor gene family members (TFF1, TFF2 and TFF3) were identified as MC histotype-specific biomarkers using RNA sequencing (RNA-seq) data for 95 stage I-II OCs. The diagnostic value of TFF1, TFF2 and TFF3 was then evaluated by immunohistochemistry on 206 stage I-II OCs stratified by histotype (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], clear cell carcinoma [CCC], and MC). Results: We showed significantly elevated intracytoplasmic protein expression levels for TFF1, TFF2 and TFF3 in MC samples, thereby revealing an association between expression of Trefoil factor gene family members and the MC histotype. Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Conclusion: Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Moreover, these novel histotype-specific diagnostic biomarkers may not only improve patient stratification of early-stage ovarian carcinomas but may also be candidates for the development of molecular targeted therapies. [ABSTRACT FROM AUTHOR]

Purpose of the study. Was was the creation of a Patient Derived Xenograft (PDX) model of non‑small cell lung cancer in immunodeficient mice adapted to growth in immunodeficient mice.Materials and methods. The study was performed using the tumor material from 14 donors implanted subcutaneously to 132 immunodeficient Balb/c Nude mice. Xenografts were maintained until the third passage. PDXs in the third passage from 3 patients were used to assess the model sensitivity to cisplatin. A histological analysis and genetic tests for the presence of EGFR mutations were performed for donor tumors from 3 patients and the corresponding xenografts in the third passage.Results. We observed a noticeable PDX growth already on the 8th day after the tumor material implantation. Successful xenograft engraftment was noted in 21 of 42 mice (50 %), which were rather successful results. A comparative histological analysis of tumor material from 3 patients showed that the PDX models retained the original histotype. We also demonstrated the identity of the EGFR mutations in the established xenografts from 3 patients and the donor tumors, which proved the value of these PDX models for preclinical studies of substances with potential antitumor activity. The analysis of the xenograft sensitivity to cytostatic cisplatin showed a statistically significant decrease in the growth rate in the xenografts obtained from 2 out of 3 patients, in comparison with the control.Conclusions. The created PDX models can be recommended as test systems for preclinical studies of the effectiveness of new pharmacological substances with potential antitumor activity.

This study investigated the incidence, mortality, and 5-year survival rates of testicular cancers diagnosed in a northern Italian province, which were eventually associated with previous or subsequent extratesticular neoplasms. Cases from 1996 to 2020 were examined by age and histotype (seminoma vs. non-seminoma). The standardized incidence rate was calculated using the European population, and the annual percent change (APC) was reported. The five-year relative survival was estimated using the Pohar Perme method. The association with the second neoplasm was also evaluated. In our study, 385 patients with testicular cancer were included, most of whom were aged between 30 and 40 years. The non-seminoma and seminoma groups accounted for 44% and 18% of younger adults, respectively. The incidence rate increased during the study period (APC 1.6*); however, it increased in seminomas (APC 2.3*) but not in non-seminomas (APC −0.1). Conversely, the mortality rate remained constantly low either overall or in each of the two groups. The overall 5-year survival rate of testicular cancer patients was 95% (99% and 88% for seminomas and non-seminomas, respectively). Primary extratesticular tumors were documented in 37 cases, 18 after and 19 before the testicular cancer diagnosis. Our study confirms that the increased incidence and excellent survival rate are the prerogative of seminomas.

IntroductionOvarian cancer (OC) is the leading cause of gynecological cancer-related death. Of the main OC histologic subtypes, invasive mucinous carcinomas (MC) account for only 3% of OC cases and are frequently associated with favorable prognosis. Nevertheless, MCs differ greatly from the other OC histotypes in clinical, pathological, and biological behavior. However, the origin and molecular pathogenesis of MC are not yet fully understood. Therefore, identification of novel diagnostic markers could potentially facilitate early diagnosis of OC, particularly the MC histotype, thereby leading to the development of histotype-specific treatment regimens and improved survival rates.MethodsIn the present study, Trefoil factor gene family members (TFF1, TFF2 and TFF3) were identified as MC histotype-specific biomarkers using RNA sequencing (RNA-seq) data for 95 stage I-II OCs. The diagnostic value of TFF1, TFF2 and TFF3 was then evaluated by immunohistochemistry on 206 stage I-II OCs stratified by histotype (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], clear cell carcinoma [CCC], and MC).ResultsWe showed significantly elevated intracytoplasmic protein expression levels for TFF1, TFF2 and TFF3 in MC samples, thereby revealing an association between expression of Trefoil factor gene family members and the MC histotype. Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype.ConclusionTaken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Moreover, these novel histotype-specific diagnostic biomarkers may not only improve patient stratification of early-stage ovarian carcinomas but may also be candidates for the development of molecular targeted therapies.

Pilomatrix-like high-grade endometrioid carcinoma (PiMHEC) has recently been described as an aggressive variant of endometrial carcinoma. Herein, we described a case of ovarian PiMHEC, comparing it to endometrial PiMHEC and assessing previously published cases of putative ovarian PiMHEC. A 65-year-old woman underwent hysterectomy for an ovarian tumor characterized by solid nests of basaloid cells with prominent ghost cell keratinization. Immunohistochemistry showed nuclear β-catenin and CDX2 expression and loss of estrogen and progesterone receptors and PAX8. These features were consistently observed in all previously published cases and may represent diagnostic criteria of PiMHEC. Other frequent features were geographic necrosis and a low-grade endometrioid component. CK7, neuroendocrine, and basal/squamous markers were inconsistently expressed. All cases with available follow-up showed poor prognosis. PiMHEC should be distinguished from mimickers, such as high-grade endometrioid carcinoma with geographic necrosis, low-grade endometrioid carcinoma with ghost cell keratinization, and undifferentiated/dedifferentiated carcinoma. In conclusion, PiMHEC can also occur in the ovary and shows several consistent clinical, morphological, and immunophenotypical features. These features support that PiMHEC is a distinct entity requiring an aggressive management. [ABSTRACT FROM AUTHOR]

Purpose: Ampullary carcinomas (ACs) are classified as pancreatobiliary (Pb-AC), intestinal (Int-AC), or mixed (Mixed-AC). The influencing role of AC subtypes on long-term outcomes is still matter of debate. Aim of this study is to evaluate the prognostic role of the three histological variants on the overall (OS) and disease-free survival (DFS) after pancreaticoduodenectomy(PD). Methods: All PDs for AC between 2004 and 2020 were included. Patients were classified according to the histological feature in Pb-AC, Int-AC, and Mixed-AC. Five-year OS and DFS were compared among the subtypes. Additionally, the prognostic role of the histological classification on OS and DFS was evaluated. Results: Fifty-six (48.7%) Pb-ACs, 53 (46.1%) Int-ACs, and 6 (5.2%) Mixed-ACs were evaluated. A poorer 5-year OS was evidenced for the Pb-AC group (54.1%) as compared to the Int-AC cohort (80.7%) (p = 0.03), but similar to the Mixed-AC population (33%) (p = 0.45). Pb-AC presented a worse 5-year DFS (42.3%) in comparison to the Int-AC (74.8%) (p = 0.002), while no difference was evidenced in comparison to the Mixed-AC (16.7%) (p = 0.51). At the multivariate analysis, the Pb-/Mixed-AC histotype was recognized as negative prognostic factor for both OS (OR: 2.29, CI: 1.05–4.98; p = 0.04) and DFS (OR: 2.17, CI: 1–4.33; p = 0.02). Conclusion: Histological subtypes of AC play a relevant role in long-term outcomes after PD. Pb-ACs and Mixed-ACs show a more aggressive tumor biology and a consequent worse survival as compared to the Int-AC subtype. [ABSTRACT FROM AUTHOR]

The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and "no specific molecular profile" (NSMP), have recently been integrated into ESGO-ESTRO-ESP guidelines. The POLE-mutant and MMR-deficient groups are associated with high mutational load, morphological heterogeneity, and inflammatory infiltration. These groups are frequent in high-grade endometrioid, undifferentiated/dedifferentiated, and mixed histotypes. POLE-mutant ECs show good prognosis and do not require adjuvant treatment, although the management of cases at stage >II is still undefined. MMR-deficient ECs show intermediate prognosis and are currently substratified based on clinicopathological variables, some of which might not have prognostic value. These groups may benefit from immunotherapy. P53-mutant ECs are typically high-grade and often morphologically ambiguous, accounting for virtually all serous ECs, most carcinosarcomas and mixed ECs, and half of clear-cell ECs. They show poor prognosis and are treated with chemoradiotherapy; a subset may benefit from HER2 inhibitors or PARP inhibitors. The NSMP group is the most frequent TCGA group; its prognosis is highly variable and affected by clinicopathological/molecular factors, most of which are still under evaluation. In conclusion, the TCGA classification has improved diagnosis, risk stratification, and management of EC. Further studies are needed to resolve the points of uncertainty that still exist. [ABSTRACT FROM AUTHOR]

The methionine (M)—valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion strains, named M1, M2C, M2T, V2, and V1, based on two major conformations of the pathological prion protein (PrPSc, type 1 and type 2), and the codon 129 genotype determining susceptibility and propagation efficiency. While the most frequent sCJD strains have been described in codon 129 homozygosis (MM1, MM2C, VV2) and heterozygosis (MV1, MV2K, and MV2C), the V1 strain has only been found in patients carrying VV. We identified six sCJD cases, 4 in Catalonia and 2 in Italy, carrying MV at PRNP codon 129 in combination with PrPSc type 1 and a new clinical and neuropathological profile reminiscent of the VV1 sCJD subtype rather than typical MM1/MV1. All patients had a relatively long duration (mean of 20.5 vs. 3.5 months of MM1/MV1 patients) and lacked electroencephalographic periodic sharp-wave complexes at diagnosis. Distinctive histopathological features included the spongiform change with vacuoles of larger size than those seen in sCJD MM1/MV1, the lesion profile with prominent cortical and striatal involvement, and the pattern of PrPSc deposition characterized by a dissociation between florid spongiform change and mild synaptic deposits associated with coarse, patch-like deposits in the cerebellar molecular layer. Western blot analysis of brain homogenates revealed a PrPSc type 1 profile with physicochemical properties reminiscent of the type 1 protein linked to the VV1 sCJD subtype. In summary, we have identified a new subtype of sCJD with distinctive clinicopathological features significantly overlapping with those of the VV1 subtype, possibly representing the missing evidence of V1 sCJD strain propagation in the 129MV host genotype. [ABSTRACT FROM AUTHOR]

Objectives: Incidence rates of thyroid cancer have dramatically increased over recent decades in many countries, particularly the papillary histotype and microcarcinomas. We examined thyroid cancer incidence and trends by demographic and tumor characteristics based on 1443 patients with thyroid cancer diagnosed between 1993 and 2013 in Oran district, in Northwest Algeria. Methods: All thyroid cancer cases were abstracted from medical records and pathology reports and classified according to the International Classification for Diseases in Oncology, third edition. Age-specific, age-standardized incidence rates per 100 000 person-years, and annual percent changes (APC) in the incidence were calculated. Results: Age-standardized incidence was 11.7 per 100 000 for women and 2.0 per 100 000 for men. Thyroid cancer incidence increased over time significantly in women (APC: +3.72%; P  < 0.05), mostly due to an increased incidence of the papillary histotype (APC: +5.48%; P  < 0.05), and microcarcinomas (APC: +17.34%; P  < 0.05). During the same time period, the incidence of follicular thyroid carcinomas decreased (APC: −3.74%; P  < 0.05). Conclusions: The results of our study showing an upward trend of thyroid cancer incidence driven largely by increases in the papillary histotype are consistent with previous studies. The higher increase has coincided with the introduction of fine needle aspiration and thyroid ultrasound in the 1990s, and may have led to overdiagnosis. However, the increased papillary-to-follicular ratio observed over time is possibly a late effect of iodine supplementation implemented in Algeria in 1967 to combat endemic goiter. Further larger-scale population-based research is needed to gain insight into thyroid cancer etiology. [ABSTRACT FROM AUTHOR]

Abstract Current classifications of sporadic Creutzfeldt–Jakob disease (sCJD) identify five subtypes associated with different disease phenotypes. Most of these histopathological phenotypes (histotypes) co-distribute with distinct pairings of methionine (M)/valine (V) genotypes at codon 129 of the prion protein (PrP) gene and the type (1 or 2) of the disease-associated PrP (PrPD). Types 1 and 2 are defined by the molecular mass (~ 21 kDa and ~ 19 kDa, respectively) of the unglycosylated isoform of the proteinase K-resistant PrPD (resPrPD). We recently reported that the sCJDVV1 subtype (129VV homozygosity paired with PrPD type 1, T1) shows an electrophoretic profile where the resPrPD unglycosylated isoform is characterized by either one of two single bands of ~ 20 kDa (T120) and ~ 21 kDa (T121), or a doublet of ~ 21–20 kDa (T121−20). We also showed that T120 and T121 in sCJDVV have different conformational features but are associated with indistinguishable histotypes. The presence of three distinct molecular profiles of T1 is unique and raises the issue as to whether T120 and T121 represent distinct prion strains. To answer this question, brain homogenates from sCJDVV cases harboring each of the three resPrPD profiles, were inoculated to transgenic (Tg) mice expressing the human PrP-129M or PrP-129V genotypes. We found that T120 and T121 were faithfully replicated in Tg129V mice. Electrophoretic profile and incubation period of mice challenged with T121−20 resembled those of mice inoculated with T121 and T120, respectively. As in sCJDVV1, Tg129V mice challenged with T121 and T120 generated virtually undistinguishable histotypes. In Tg129M mice, T121 was not replicated while T120 and T121−20 generated a ~ 21–20 kDa doublet after lengthier incubation periods. On second passage, Tg129M mice incubation periods and regional PrP accumulation significantly differed in T120 and T121−20 challenged mice. Combined, these data indicate that T121 and T120 resPrPD represent distinct human prion strains associated with partially overlapping histotypes.

To improve the precision of epithelial ovarian cancer histotyping, Köbel et al. (2016) developed immunohistochemical decision-tree algorithms. These included a six- and four-split algorithm, and separate six-split algorithms for early- and advanced stage disease. In this study, we evaluated the efficacy of these algorithms. A gynecological pathologist determined the hematoxylin and eosin (H&E)-based histotypes of 230 patients. Subsequently, the final histotypes were established by re-evaluating the H&E-stained sections and immunohistochemistry outcomes. For histotype prediction using the algorithms, the immunohistochemical markers Napsin A, p16, p53, progesterone receptor (PR), trefoil factor 3 (TFF3), and Wilms' tumor 1 (WT1) were scored. The algorithmic predictions were compared with the final histotypes to assess their precision, for which the early- and advanced stage algorithms were assessed together as six-split-stages algorithm. The six-split algorithm demonstrated 96.1% precision, whereas the six-split-stages and four-split algorithms showed 93.5% precision. Of the 230 cases, 16 (7%) showed discordant original and final diagnoses; the algorithms concurred with the final diagnosis in 14/16 cases (87.5%). In 12.4%-13.3% of cases, the H&E-based histotype changed based on the algorithmic outcome. The six-split stages algorithm had a lower sensitivity for low-grade serous carcinoma (80% versus 100%), while the four-split stages algorithm showed reduced sensitivity for endometrioid carcinoma (78% versus 92.7-97.6%). Considering the higher sensitivity of the six-split algorithm for endometrioid and low-grade serous carcinoma compared with the four-split and six-split-stages algorithms, respectively, we recommend the adoption of the six-split algorithm for histotyping epithelial ovarian cancer in clinical practice., Competing Interests: Declaration of competing interest The authors have no competing interests to declare relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

According to the 2019 WHO classification of breast tumors, neuroendocrine neoplasms (NENs) are classified into well-differentiated NE tumors (NET) and poorly differentiated NE carcinomas (NEC), while other breast cancers (BCs) of special and no special type with neuroendocrine (NE) features are not incorporated in this scheme anymore. We aimed to assess whether INSM1, a novel NE marker, could have a role in breast NEN subtyping. We selected 63 BCs operated from 2003 to 2018, classified as BCs with NE features, with available clinico-pathological data. Following 2019 WHO criteria, this cohort was reclassified into 37 NETs/NECs, the remaining 26 tumors representing solid-papillary (7), mucinous (7), and mixed type (12) carcinomas with NE differentiation. Chromogranin A (CGA) and synaptophysin (SYN) immunostains were reviewed, and INSM1 was tested by immunohistochemistry. Thirty CGA- and SYN-negative no special type BCs served as negative control. INSM1 was expressed in 52/63 cases of the whole cohort (82.54%). INSM1 positive and negative cases had no significantly different clinico-pathological characteristics. INSM1 expression was not significantly different between the newly reclassified NET/NEC group and other BCs with NE features. No immunoexpression was observed in control BCs. The sensitivity and specificity of INSM1 for the NE phenotype was 82.5% and 100%, respectively, compared to 61.9% and 100% for CGA, and 95.2 and 100% for SYN. In conclusion, INSM1 is as accurate as traditional NE biomarkers to identify NE differentiation in BC. In analogy to standard NE markers, INSM1 could not distinguish NET and NEC from the other BC histotypes with NE differentiation. [ABSTRACT FROM AUTHOR]

Current classifications of sporadic Creutzfeldt–Jakob disease (sCJD) identify five subtypes associated with different disease phenotypes. Most of these histopathological phenotypes (histotypes) co-distribute with distinct pairings of methionine (M)/valine (V) genotypes at codon 129 of the prion protein (PrP) gene and the type (1 or 2) of the disease-associated PrP (PrPD). Types 1 and 2 are defined by the molecular mass (~ 21 kDa and ~ 19 kDa, respectively) of the unglycosylated isoform of the proteinase K-resistant PrPD (resPrPD). We recently reported that the sCJDVV1 subtype (129VV homozygosity paired with PrPD type 1, T1) shows an electrophoretic profile where the resPrPD unglycosylated isoform is characterized by either one of two single bands of ~ 20 kDa (T120) and ~ 21 kDa (T121), or a doublet of ~ 21–20 kDa (T121−20). We also showed that T120 and T121 in sCJDVV have different conformational features but are associated with indistinguishable histotypes. The presence of three distinct molecular profiles of T1 is unique and raises the issue as to whether T120 and T121 represent distinct prion strains. To answer this question, brain homogenates from sCJDVV cases harboring each of the three resPrPD profiles, were inoculated to transgenic (Tg) mice expressing the human PrP-129M or PrP-129V genotypes. We found that T120 and T121 were faithfully replicated in Tg129V mice. Electrophoretic profile and incubation period of mice challenged with T121−20 resembled those of mice inoculated with T121 and T120, respectively. As in sCJDVV1, Tg129V mice challenged with T121 and T120 generated virtually undistinguishable histotypes. In Tg129M mice, T121 was not replicated while T120 and T121−20 generated a ~ 21–20 kDa doublet after lengthier incubation periods. On second passage, Tg129M mice incubation periods and regional PrP accumulation significantly differed in T120 and T121−20 challenged mice. Combined, these data indicate that T121 and T120 resPrPD represent distinct human prion strains associated with partially overlapping histotypes. [ABSTRACT FROM AUTHOR]

Abstract Objectives Among women with epithelial ovarian cancer (EOC), histotype is one of the major prognostic factors. However, few data are available on histotype- specific survival and mortality estimates among these patients. We therefore examined survival and causes of death among women with EOC by histotype. Methods A population- based cohort including all ovarian cancer patients diagnosed in British Columbia (BC) between 1990 and 2014 was built using population-based administrative datasets. We compared causes of death within histotypes, by age at diagnosis, BRCA status, and time since diagnosis. Results A total of 6975 women were identified as having been diagnosed with EOC between 1990 and 2014 in BC. The most common cause of death among these women was ovarian cancer until 10 years post diagnosis when other causes surpassed ovarian cancer as the leading cause of death. Among women with serous EOCs, ovarian cancer was the leading cause of death 12 years after diagnosis, whereas ovarian cancer was the leading cause of death for 8 years among women with non- serous EOCs. Among women with serous EOCs, ovarian cancer was the leading cause of death for 12 years among younger women ( = 60 years of age, and those with BRCA mutations were more likely to die from ovarian cancer than those without a BRCA mutation. Conclusions Within 10 years from diagnosis, ovarian cancer is the leading cause of death among women diagnosed with EOC.

Background and objective So far there’s no tumor maker applied in diagnosis and treatment of thymic epithelial tumors. This study is to assess the correlation between serum cytokine 19 fragment (Cyfra 21-1) and clinicopathological features and prognosis of thymic epithelial tumors (TETs). Methods The clinical data of 159 patients with TETs in Shanghai Chest Hospital was retrospectively analysed. Patients were divided into groups according to different tumor stages and histotypes. Serum Cyfra 21-1 was thus compared. In addition, the possible relationship between perioperative serum Cyfra 21-1 level and the recurrent status was carrid out. Results Preoperative Cyfra 21-1 serum concentrations in patiants with advanced stage (T4) and thymic carcinomas were significantly higher than that in others (P

Abstract Background Ovarian carcinoma is the most lethal gynecological malignancy due to early dissemination and acquired resistance to platinum-based chemotherapy. Reliable markers that are independent and complementary to clinical parameters are needed to improve the management of patients with this disease. The Canadian Ovarian Experimental Unified Resource (COEUR) provides researchers with biological material and associated clinical data to conduct biomarker validation studies. Using standards defined by the Canadian Tissue Repository Network (CTRNet), we have previously demonstrated the quality of the biological material from this resource. Here we describe the clinical characteristics of the COEUR cohort. Methods With support from 12 Canadian ovarian cancer biobanks in Canada, we created a central retrospective cohort comprised of more than 2000 patient tissue samples with associated clinical data, including 1246 high-grade serous, 102 low-grade serous, 295 endometrioid, 259 clear cell and 89 mucinous carcinoma histotypes. A two-step reclassification process was applied to assure contemporary histological classification (histotyping). For each histotypes individually, we evaluated the association between the known clinico-pathological parameters (stage, cytoreduction, chemotherapy treatment, BRCA1 and BRCA2 mutation) and patient outcome by using Kaplan-Meier and Cox proportional hazard regression analyses. Results The median follow-up time of the cohort was 45 months and the 5-year survival rate for patients with high-grade serous carcinomas was 34%, in contrast to endometrioid carcinomas with 80% at 5 years. Survival profiles differed by histotype when stratified by stage or cytoreduction. Women with mucinous or clear cell carcinomas at advanced stage or with non-optimally debulked disease had the worst outcomes. In high-grade serous carcinoma, we observed significant association with longer survival in women harboring BRCA1 or BRCA2 mutation as compared to patients without detectable mutation. Conclusions Our results show the expected survival rates, as compared with current literature, in each histotype suggesting that the cohort is an unbiased representation of the five major histotypes. COEUR, a one stop comprehensive biorepository, has collected mature outcome data and relevant clinical data in a comprehensive manner allowing stratified analysis.

This study describes and illustrates the jaws, teeth, and tooth microstructure of the Prickly Dogfish Oxynotus bruniensis. Detailed accounts of the dental morphology of O. bruniensis are rare and have not addressed the tissue arrangement or microstructure of the teeth. These features are documented and discussed in the contexts of interspecific comparisons with other elasmobranchs and the dietary specialization of O. bruniensis. The overall tooth morphology of O. bruniensis is similar to those of other closely related members in the order Squaliformes, as is the tissue arrangement, or histotype. Oxynotus bruniensis exhibits a simplified enameloid microstructure, which we compare with previously documented enameloid microstructures of other elasmobranchs. Though subtle interspecific differences in dental characters are documented, neither overall tooth morphology nor histotype and microstructure are unique to O. bruniensis. We conclude that in the case of O. bruniensis, dietary specialization is facilitated by behavioral rather than morphological specialization. [ABSTRACT FROM AUTHOR]

Background: Controversies exist regarding the biopsy technique of choice for the accurate diagnosis of soft‐tissue sarcoma (STS). The objective of this systematic review and meta‐analysis was to compare the diagnostic accuracy of core needle biopsy (CNB) versus incisional biopsy (IB) in STS with reference to the final histopathological result. Methods: Studies regarding the diagnostic accuracy of CNB and IB in detecting STS were searched systematically in the MEDLINE and EMBASE databases. Estimates of sensitivity and specificity with associated 95% CIs for diagnostic accuracy were calculated. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS‐2). Results: A total of 17 studies comprising 2680 patients who underwent 1582 CNBs and 241 IBs with subsequent tumor resection met the inclusion criteria. The sensitivity and specificity of CNB and IB to detect the dignity of lesions were 97% (95% CI, 95%‐98%) and 99% (95% CI, 97%‐99%), respectively, and 96% (95% CI, 92%‐99%) and 100% (95% CI, 94%‐100%), respectively. Estimates of the sensitivity and specificity of CNB and IB to detect the STS histotype were 88% (95% CI, 86%‐90%) and 77% (95% CI, 72%‐81%), respectively, and 93% (95% CI, 87%‐97%) and 65% (95% CI, 49%‐78%), respectively. Patients who underwent CNB had a significantly reduced risk of complications compared with patients who underwent IB (risk ratio, 0.14; 95% CI, 0.03‐0.56 [P ≤.01). Quality assessment of studies revealed a high risk of bias. Conclusions: CNB has high accuracy in diagnosing the dignity of lesions and STS histotype in patients with suspected STS with fewer complications compared with IB. Therefore, CNB should be regarded as the primary biopsy technique. A systematic summary of the current literature demonstrates that core needle biopsy is the superior method with which to differentiate soft‐tissue sarcoma subtypes, with lower rates of complications compared with the incision biopsy technique. Core needle biopsy should be regarded as the primary biopsy technique. [ABSTRACT FROM AUTHOR]

During their evolutionary history, modern sharks developed different tooth mineralization patterns that resulted in very distinct histological patterns of the tooth crown (histotypes). To date, three different tooth histotypes have been distinguished: (i) orthodont teeth, which have a central hollow pulp cavity in the crown, encapsulated by a prominent layer of dentine (orthodentine); (ii) pseudoosteodont teeth, which have their pulp cavities secondarily replaced by a dentinal core of porous dentine (osteodentine), encased by orthodentine; and (iii) osteodont teeth, which lack orthodentine and the whole tooth crown of which consists of osteodentine. The aim of the present study was to trace evolutionary trends of tooth mineralization patterns in modern sharks and to find evidence for the presence of phylogenetic or functional signals. High resolution micro‐computed tomography images were generated for the teeth of members of all nine extant shark orders and the putative stem group †Synechodontiformes, represented here by three taxa, to examine the tooth histology non‐destructively. Pseudoosteodonty is the predominant state among modern sharks and represents unambiguously the plesiomorphic condition. Orthodonty evolved several times independently in modern sharks, while the osteodont tooth histotype is only developed in lamniform sharks. The two shark orders Heterodontiformes and Pristiophoriformes showed highly modified tooth histologies, with Pristiophorus exhibiting a histology only known from batomorphs (i.e. rays and skates), and Heterodontus showing a histological difference between anterior and posterior teeth, indicating a link between its tooth morphology, histology and durophagous lifestyle. The tooth histotype concept has proven to be a useful tool to reflect links between histology, function and its taxonomic value for distinct taxa; however, a high degree of variation, especially in the pseudoosteodont tooth histotype, demonstrates that the current histotype concept is too simplistic to fully resolve these relationships. The vascularization pattern of the dentine might offer new future research pathways for better understanding functional and phylogenetic signals in the tooth histology of modern sharks. [ABSTRACT FROM AUTHOR]

In sporadic Creutzfeldt-Jakob disease, molecular subtypes are neuropathologically well identified by the lesioning profile and the immunohistochemical PrPd deposition pattern in the grey matter (histotypes). While astrocytic PrP pathology has been reported in variant CJD and some less frequent histotypes (e.g., MV2K), oligodendroglial pathology has been rarely addressed. We assessed a series of sCJD cases with the aim to identify particular histotypes that could be more prone to harbor oligodendroglial PrPd. Particularly, the MM2C phenotype, in both its more “pure” and its mixed MM1+2C or MV2K+2C forms, showed more frequent oligodendroglial PrP pathology in the underlying white matter than the more common MM1/MV1 and VV2 histotypes, and was more abundant in patients with a longer disease duration. We concluded that the MM2C strain was particularly prone to accumulate PrPd in white matter oligodendrocytes.

Penile squamous cell carcinoma is a rare malignancy with various distinct histological subtypes, each with distinct appearances, histotypic specific associations with human papillomavirus (HPV) and clinical behaviour. Despite a wealth of pathological knowledge, there still remains a limited understanding of the fundamental molecular drivers that govern penile carcinogenesis with their underlying prognostic and therapeutic importance. However, recent work has improved our fundamental understanding of the molecular pathogenesis of penile cancer: commonly divided into the HPV-dependent and HPV-independent pathways. This review aims to summarise current developments in the histopathology and the molecular pathogenesis of penile cancer, with the advent of next-generation sequencing, and the opportunities for the targeting of molecular drivers of metastatic disease. [ABSTRACT FROM AUTHOR]

Aim: To investigate clinicopathological parameters and histotype-specific survival of epithelial ovarian cancer by stage using the 2014 WHO classification. Patients & methods: Patients were obtained from the SEER database. Multivariate and univariate Cox regression analyses were applied to assess survival outcomes. Results: Irrespective of stages, low-grade serous and endometrioid had the best survival rates. In localized and regional stages, the poorest survival rates were detected for carcinosarcoma and malignant Brenner tumors, but in distant stage, the worst prognoses were observed in mucinous, clear cell and carcinosarcoma (p < 0.05 for all). Conclusion: Our study displayed significant differences in clinicopathological parameters and histotype-specific survival by stages that reflected current consensus on histotype classification and pathogenesis of epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Objectives: Among women with epithelial ovarian cancer (EOC), histotype is one of the major prognostic factors. However, few data are available on histotype- specific survival and mortality estimates among these patients. We therefore examined survival and causes of death among women with EOC by histotype.Methods: A population- based cohort including all ovarian cancer patients diagnosed in British Columbia (BC) between 1990 and 2014 was built using population-based administrative datasets. We compared causes of death within histotypes, by age at diagnosis, BRCA status, and time since diagnosis.Results: A total of 6975 women were identified as having been diagnosed with EOC between 1990 and 2014 in BC. The most common cause of death among these women was ovarian cancer until 10 years post diagnosis when other causes surpassed ovarian cancer as the leading cause of death. Among women with serous EOCs, ovarian cancer was the leading cause of death 12 years after diagnosis, whereas ovarian cancer was the leading cause of death for 8 years among women with non- serous EOCs. Among women with serous EOCs, ovarian cancer was the leading cause of death for 12 years among younger women (< 60 years of age) compared to 8 years among women > = 60 years of age, and those with BRCA mutations were more likely to die from ovarian cancer than those without a BRCA mutation.Conclusions: Within 10 years from diagnosis, ovarian cancer is the leading cause of death among women diagnosed with EOC. [ABSTRACT FROM AUTHOR]

Abstract Objective Major changes in the classification of ovarian carcinoma histotypes occurred over the last two decades, resulting in the current 2014 World Health Organization (WHO) diagnostic criteria that recognize five principal histotypes: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. We assessed the impact of these guidelines and use of immunohistochemical (IHC) markers on classification of ovarian carcinomas in existing population-based studies. Methods We evaluated histotype classification for 2361 ovarian carcinomas diagnosed between 1999 and 2009 from two case-control studies using three approaches: 1. pre-2014 WHO ("historic") histotype; 2. Standardized review of pathology slides using the 2014 WHO criteria alone; and 3. An integrated IHC assessment along with the 2014 WHO criteria. We used Kappa statistics to assess agreement between approaches, and Kaplan-Meier survival curves and Cox proportional hazards models to evaluate mortality. Results Compared to the standardized pathologic review histotype, agreement across approaches was high (kappa = 0.892 for historic, and 0.849 for IHC integrated histotype), but the IHC integrated histotype identified more low-grade serous carcinomas and a subset of endometrioid carcinomas that were assigned as high-grade serous (n = 25). No substantial differences in histotype-specific mortality were observed across approaches. Conclusions Our findings suggest that histotype assignment is fairly consistent regardless of classification approach, but that progressive improvements in classification accuracy for some less common histotypes are achieved with pathologic review using the 2014 WHO criteria and with IHC integration. We additionally recommend a classification scheme to fit historic data into the 2014 WHO categories to answer histotype-specific research questions. Highlights • Older studies can reclassify histotypes to align with the new guidelines. • Survival patterns are generally similar across histotype assignment approaches. • The most notable differences in classification were for the less common histotypes. [ABSTRACT FROM AUTHOR]

Abstract Background The addition of human epididymis protein 4 (HE4) to carbohydrate antigen 125 (CA125) in ovarian cancer (OC) assessment has been proposed. We compared the clinical value of biomarker changes in a prospective series of patients undergoing OC monitoring. Methods We studied 43 patients (79% post-menopausal), followed for 3.5 ± 3.1 years. Serous OC was prevalent (53.5%), with 81.4% of patients diagnosed at late stages. Both cut-offs and reference change values (RCV) were used for assessing significant marker changes. Results The use of cut-offs for CA125 and HE4 interpretation appeared equally fitting the evaluation of disease progression defined according to running guidelines, performing better than RCV criterion. However, both markers were simultaneously over cut-offs only in 46% of samples and changed in agreement in 35% of cases. The inspection of individual longitudinal trends indicated as main causes of disagreement the influence of renal impairment on HE4 concentrations and the more significant rate of decrease of CA125 vs. HE4 concentrations early after treatment. CA125 and HE4 changes according to RCV were not predictive of OC progression. Conclusions CA125 appears the most reliable biomarker for OC monitoring, whereas HE4 contributes additional information only in a minority of cases. Highlights • We compared CA125 and HE4 changes in ovarian cancer monitoring. • The use of cut-offs for CA125 and HE4 interpretation equally fitted the evaluation of disease progression. • CA125 and HE4 in the ovarian cancer follow-up may disagree for renal impairment/response to treatment. [ABSTRACT FROM AUTHOR]

Background Grade and histotype of ovarian carcinomas are often used as surrogates of molecular subtypes. We examined factors affecting pathologists' reproducibility in two prospective studies. Methods Two pathologists independently reviewed slides from 459 incident ovarian cancers in the Nurses' Health Study (NHS) and NHSII. We described agreement on tumor characteristics using percent agreement and Cohen's standard kappa (κ) coefficients. We used logistic regression, with disagreement as the outcome, to evaluate the contribution of case and tumor characteristics to agreement. Results Inter-rater agreement was 95% (κ = 0.81) for carcinoma versus borderline, 89% (κ = 0.58) for grade and 85% (κ = 0.71) for histotype. Inter-rater grading disagreement was higher for non-serous histotypes (OR = 4.66, 95% CI 2.09–10.36) and lower for cancers with bizarre atypia (OR = 0.13, 95% CI 0.04–0.38). Agreement with original pathology reports was 94% (κ = 0.73) for carcinoma versus borderline, 78% (κ = 0.60) for histotype, and 79% (κ = 0.24) for grade. Grading disagreement was significantly lower for tumors with ‘solid, pseudoendometrioid or transitional’ (SET) architecture (OR = 0.08, 95%CI 0.01–0.84). Date of original diagnosis, hospital type, number of slides available for review, tumor stage, and slide quality were not related to agreement. Conclusion Overall, inter-rater agreement for tumor type and grade for archival tissue specimens was good. Agreement between the consensus review and original pathology reports was lower. Factors contributing to grading disagreement included non-serous histotype, absence of bizarre atypia, and absence of SET architecture. [ABSTRACT FROM AUTHOR]

Abstract Purpose To detect fat status and differentiate histotypes of renal masses by using Dixon technique. Materials and methods This study included 134 solid renal masses. Signal intensity index (SII) and fat fraction (FF) in different histotypes were compared. Results Only angiomyolipoma (AML), clear cell renal cell carcinoma (RCC), and papillary RCC were confirmed to contain fat. The FF of 16.8% can effectively differentiate AML from clear cell RCC, so did the SII of 9.2% can differentiate clear cell RCC from non-clear cell RCC and rare benign histotypes. Conclusion Dixon technique successfully evaluated the fat status and histotypes of renal masses. Highlights • Dixon technique systematically assessed renal masses: fat status and histotypes. • Only three histotypes of solid renal masses were confirmed to contain fat. • Signal intensity index and fat fraction had significant difference among histotypes. • Signal intensity index and fat fraction can differentiate different histotypes. [ABSTRACT FROM AUTHOR]

Background To investigate the role of Kodama PenA subtype in influencing survival in patients with early gastric cancer (EGC). Methods All patients surgically treated for EGC at 7 Italian centers (Forlì, Varese, Siena, Verona, Milan, Rome and Perugia) belonging to the Italian Research Group for Gastric Cancer (GIRCG) from January 1982 and December 2009 were included. Results PenA patients were 230 (21.5%) while other types were 839 (78.5%). Nodal metastases were more common in PenA (30.7%) than non-PenA (10.4%) EGCs. Among preoperative variables, only age (OR 1.02; 95% CI 1.00–1.03, p = 0.009) and macrotype III (OR 1.95; 95% CI 1.39–2.75, p = 0.0001) were significantly associated with Pen A type. Survival analysis performed on N0 patients demonstrated that only size >2 cm (HR 1.85; 95% CI 1.12–3.05, p = 0.017) and age (HR 1.06; 95% CI 1.03–1.08, p < 0.0001) were independent poor prognostic factor. Among N+ patients age (HR 1.04; 95% CI 1.00–1.07, p = 0.048), number of positive lymph nodes (HR 1.13; 95% CI 1.05–1.20, p = 0.0002) and PenA (HR 4.23; 95% CI 1.70–10.55, p = 0.002) were significantly correlated with poor prognosis at multivariate analysis. Conclusions Kodama PenA subtype was the most powerful independent prognostic factor in patients with nodal metastases. Its status should always be investigated in EGCs patients. [ABSTRACT FROM AUTHOR]

Background: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs.Methods: Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]).Results: ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P < .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups.Conclusions: Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802-13. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: There is substantial evidence that a virus homologous to mouse mammary tumor virus (MMTV) may have a role in human breast cancer. The present study indicates that those who developed breast cancer associated with an MMTV-like virus had this virus in their non-cancerous breast tissues years before the cancer developed. Methods: Polymerase chain reaction (PCR) techniques and sequencing were used to identify MMTV-like envelope gene sequences (MMTV-like env sequences) in Australian benign breast biopsy specimens from women who several years later developed breast cancer. Murine contamination was excluded by stringent laboratory procedures, and the absence of intracisternal A particle sequences and mitochondrial cyclooxygenase sequences. Results: MMTV-like env sequences (also called HMTV sequences to denote their source) were found in 9 of 25 breast cancer specimens (36%). Among 25 non-cancerous breast biopsies of these same patients taken 1 to 11 years earlier, six contained MMTV-like sequences (24%). Five of the six were among the nine virally-associated breast cancers. In two pairs of specimens, benign and malignant, env sequences were 97% identical. Conclusions: The identification of MMTV (MMTV-like) sequences in breast tissues prior to the development of MMTV positive breast cancer fulfills a key criterion for a possible causal role for the MMTV-like virus in human breast cancer. [ABSTRACT FROM AUTHOR]